The mitochondrial-targeted antioxidant MitoQ ameliorates metabolic syndrome features in obesogenic diet-fed rats better than Apocynin or Allopurinol

Abstract

The prevalence of metabolic syndrome (MetS) components including obesity, dyslipidemia, insulin resistance (IR), and hepatic steatosis is rapidly increasing in wealthy societies. It is accepted that inflammation/oxidative stress are involved in the initiation/evolution of the MetS features. The present work was designed to evaluate the effects of three major cellular ROS production systems on obesity, glucose tolerance, and hepatic steatosis development and on oxidative stress onset. To do so, 40 young male Sprague–Dawley rats were divided into 5 groups: 1-control group, 2-high fat (HF) group (60% energy from fat), 3-HF+ MitoQ (mitochondrial ROS scavenger), 4-HF+ Apocynin (NADPH oxidase inhibitor), 5-HF+ Allopurinol (xanthine oxidase inhibitor). After 8 weeks of these treatments, surrogate MetS, mitochondrial function, and oxidative stress markers were measured in blood and liver. As expected, rats that were fed the HF diet exhibited increased body weight, glucose intolerance, overt hepatic steatosis, and increased hepatic oxidative stress. The impacts of the studied ROS inhibitors on these aspects of the MetS were markedly different. MitoQ showed the most clinically relevant effects, attenuating body weight gain and glucose intolerance provoked by the HF diet. Both Apocynin and Allopurinol showed limited effects suggesting secondary roles of xanthine oxidase (XO) or NADPH oxidase-dependent ROS production in the onset of oxidative stress-dependent obesity, glucose intolerance, and hepatic steatosis process. Thus, MitoQ revealed the central role of mitochondrial oxidative stress in the development of MetS and suggested that mitochondria-targeted antioxidants may be worth considering as potentially helpful therapies for MetS features.

Keywords::

• antioxidants
• free radicals
• hepatic steatosis
• high fat diet
• insulin resistance
• metabolic syndrome
• mitochondria
• MitoQ
• NADPH oxidase
• obesity
• oxidative stress
• xanthine oxidase

Acknowledgements

The authors acknowledge the financial support of the French Lipid Nutrition Group and the National Institute for Agronomic Research and, in particular, the Human nutrition Department (Alim-H department). The support from the side of the EU project CM0603 is also kindly acknowledged. The authors wish to thank Marie-Agnès Chauvin for completion of Oxyblot and Oxphos western blots. The authors also wish to thank the staff of the animal facilities for animal use.

Author contributions

Author contributions were as follows: study design (CF-C, JPC and CC), data collection (GF, JR, BB, BC, REE, DC, JR, KZ, MM, EB), statistical analysis (CC and CF-C), data interpretation (CF-C, NZ, EB, CC), manuscript preparation (CF-C, EB, NZ, MM, CC), literature search (CF-C and CC) funds collection (CF-C, NZ and CC). All the authors have read and approved the final version of this manuscript.

Declaration of interest

The authors report no declarations of interest. MPM holds shares in the company Antipodean Pharmaceuticals Inc., who are developing MitoQ as a therapy. The authors alone are responsible for the content and writing of the paper.